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Accurate understanding of x-ray diagnostics is crucial for both interpreting high-energy-density experiments and testing simulations through quantitative comparisons. X-ray diagnostic models are complex. Past treatments of individual x-ray diagnostics on a case-by-case basis have hindered universal diagnostic understanding. Here, we derive a general formula for modeling the absolute response of non-focusing x-ray diagnostics, such as x-ray imagers, one-dimensional space-resolved spectrometers, and x-ray power diagnostics. The present model is useful for both data modeling and data processing. It naturally accounts for the x-ray crystal broadening. The new model verifies that standard approaches for a crystal response can be good approximations, but they can underestimate the total reflectivity and overestimate spectral resolving power by more than a factor of 2 in some cases near reflectivity edge features. We also find that a frequently used, simplified-crystal-response approximation for processing spectral data can introduce an absolute error of more than an order of magnitude and the relative spectral radiance error of a factor of 3. The present model is derived with straightforward geometric arguments. It is more general and is recommended for developing a unified picture and providing consistent treatment over multiple x-ray diagnostics. Such consistency is crucial for reliable multi-objective data analyses.

Chronic complications are a significant concern for people living with HIV/AIDS (PLWHA) infection. HIV-associated neurocognitive disorders (HAND) are prevalent in PLWHA. Yet, the efficacy of medications that penetrate the central nervous system (CNS) at preventing or slowing the progression of HAND remains largely unknown. The objective of this study was to determine whether high CNS penetration effectiveness (CPE) regimens improve neurocognitive test scores in PLWHA on combined antiretroviral therapy (cART). Primary literature evaluating cognitive outcomes based on CPE score of cART regimens in PLWHA was assembled from PubMed/Medline and EMBASE. Both randomized controlled trials and observational studies with at least 12 weeks of follow-up were included. A meta-analysis was conducted to calculate the standardized mean difference. Eight trials including a total of 3,303 patients with 13,103 person-years of follow-up were included in the systematic review. Four trials (

Barotropic (i.e., depth-uniform) coastal oceanic Kelvin waves can provide rapid teleconnections from climate and weather events in one location to remote regions of the globe. Studies suggest that barotropic Kelvin waves observed around Antarctica may provide a mechanism for rapidly propagating circulation anomalies around the continent, with implications for continental shelf temperatures along the West Antarctic Peninsula and thus Antarctic ice mass loss rates. However, how the propagation of Kelvin waves around Antarctica is influenced by features such as coastal geometry and variations in bathymetry remains poorly understood. Here we study the propagation of barotropic Antarctic Kelvin waves using a range of idealized model simulations. Using a single-layer linear shallow water model with 1∘ horizontal resolution, we gradually add complexity of continental configuration, realistic bathymetry, variable planetary rotation, and forcing scenarios, to isolate sources and sinks of wave energy and the mechanisms responsible. We find that approximately 75% of sub-inertial barotropic Kelvin wave energy is scattered away from Antarctica as other waves in one circumnavigation of the continent, due mostly to interactions with bathymetry. Super-inertial barotropic Kelvin waves lose nearly 95% of their energy in one circumpolar loop, due to interactions with both coastal geometry and bathymetry. These results help to explain why only sustained signals of low-frequency resonant barotropic Kelvin waves have been observed around Antarctica, and contribute to our understanding of the role of rapid, oceanic teleconnections in climate.

Overweight and obesity increase the risk of development and progression of knee osteoarthritis (OA), with higher levels of fat mass and lower levels of lean mass associated with poorer functional status. The aim was to assess changes in weight, body composition and physical function following weight loss or weight maintenance interventions in knee OA. A comprehensive search of four databases was conducted. The risk of bias was assessed using the Quality Criteria Checklist for primary research. Primary outcomes included weight, body composition and physical function; secondary outcomes were lipids, inflammatory biomarkers and muscle strength. Eleven studies were included utilizing

Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. The one insulin bound IR adopts a Γ-shaped conformation. The two insulins bound IR assumes a Ƭ-shaped conformation. One insulin is bound at site-1 and another insulin simultaneously contacts both sites-1 and −2 in the Ƭ-shaped IR dimer. We further demonstrated that the concurrent binding of four insulins to sites-1 and −2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.

Enzyme activity is the basis for many biosensors where a catalytic event is used to detect the presence and amount of a biomolecule of interest. To create a practical point-of-care biosensor, these enzymes need to be removed from their native cellular environments and immobilized on an abiological surface to rapidly transduce a biochemical signal into an interpretable readout. This immobilization often leads to loss of activity due to unfolded, aggregated, or improperly oriented enzymes when compared to the native state. In this work, we characterize the formation and surface packing density of a stable monolayer of acetylcholinesterase (AChE) immobilized on a planar gold surface and quantify the extent of activity loss following immobilization. Using spectroscopic ellipsometry, we determined that the surface concentration of AChE on a saturated Au surface in a buffered solution was 2.77 ± 0.21 pmol cm

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Purpose Numerous clinical scoring tools exist for a variety of patient populations and disease states, but few tools provide information specifically designed for use by critical care pharmacists. The medication regimen complexity–intensive care unit (MRC-ICU) score was designed to provide high-level information about the complexity of critically ill patients’ medication regimens for use by critical care pharmacists. To date, implementation of this score in the electronic medical record (EMR) has not been reported. Summary Using an agile project management framework, the MRC-ICU score was rapidly implemented into an academic medical center’s EMR. The score is automatically calculated for all critically ill patients and is available for critical care pharmacists to triage patient review in their individual workflow. Reporting capabilities of the score also allow for granular complexity trending over time and between units, supplementing other objective measures of pharmacist workload. Conclusion The MRC-ICU score can be quickly implemented into the EMR for pharmacist use in real time. Future investigations into how pharmacists utilize this information and how to harness reporting capabilities for pharmacist workload assessment are warranted.

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 94]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 93]. Several structural forms of U-II exist in fish and amphibians [94]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [94]. The urotensinergic system displays an unprecedented repertoire of four or five ancient UT in some vertebrate lineages and five U-II family peptides in teleost fish [91].

Cell penetrating peptides (CPPs) facilitate translocation across biological membranes and are of significant biological and medical interest. Several CPPs can permeate into specific cells and organelles. We examine the incorporation and translocation of a novel anti-cancer CPP in a dioleoylphosphatidylcholine (DOPC) lipid bilayer membrane. The peptide, NAF-1(44-67), is a short fragment of a transmembrane protein, consisting of hydrophobic N terminal and charged C terminal segments. Experiments using fluorescently-labeled NAF-1(44-67) in ~100 nm DOPC vesicles and atomically detailed simulations conducted with Milestoning support a model in which a significant barrier for peptide-membrane entry is found at the interface between the aqueous solution and membrane. The initial step is the insertion of the N terminal segment and the hydrophobic helix into the membrane, passing the hydrophilic head groups. Both experiments and simulations suggest that the free energy difference in the first step of the permeation mechanism in which the hydrophobic helix crosses the phospholipid head groups is −0.4 kcal mol(−1) slightly favoring motion into the membrane. Milestoning calculations of the mean first passage time and the committor function underscore the existence of an early polar barrier followed by a diffusive barrierless motion in the lipid tail region. Permeation events are coupled to membrane fluctuations that are examined in detail. Our study opens the way to investigate in atomistic resolution the molecular mechanism, kinetics, and thermodynamics of CPP permeation to diverse membranes.

The liver performs important functions that are essential for life. If the liver fails, patients will die unless they receive a new liver from a donor (transplant). Unfortunately, there are not enough livers for everyone and some patients die while waiting for a suitable organ. This article describes a novel technique that allows resuscitation and testing of a potential donor liver so that more patients can safely receive a transplant.

We investigate positive subtropical low cloud feedback mechanisms in climate models which have performed the CMIP6/CFMIP-3 AMIP and AMIP uniform +4K experiments while saving CFMIP-3 process diagnostics on model levels. Our analysis focuses on the trade cumulus/stratocumulus transition region between California and Hawaii, where positive low cloud feedbacks are present in the JJA season. We introduce a methodology to} test various positive cloud feedback mechanisms proposed in the literature as primary explanations for the low cloud responses in the models. Causal hypotheses are tested by comparing their predictions with the models’ responses of clouds, cloud controlling factors, boundary layer depth and temperature/humidity tendencies to climate warming. Changes in boundary layer depth, relative humidity in the cloud layer and humidity advection at the top of the boundary layer are shown to distinguish among the hypotheses considered. For the cases examined, our approach rules out 4/5 of the mechanisms considered in half of the models and 3/5 in the remainder. We argue that unambiguously identifying the positive feedback mechanisms operating in models will in some cases require intervention experiments designed to test specific hypotheses.

Ovarian cancer associated ascites contains soluble inhibitory factors. The ascites was cleared of cellular debris by centrifugation as previously described (18). (A, B) The ascites was filtered 0.2 micron filter and fractionated- f1: 50. (C) The ascites was treated with 50 μg/ml proteinase K at 37{degree sign}C for 1 hour and then incubated at 95{degree sign}C for 10min to heat inactivate the enzyme. The antigen presenting cells were treated with the clarified supernantants for 4 h at 37{degree sign}C, then washed extensively with PBS, and cocultured with NKT hybridomas for 20-24 h at 37{degree sign}C. Cytokine released (IL-2) was measured as an indication of NKT cell activation and was measured by standard sandwich ELISA.

Methodology Details

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease for which better prognostic models for survival are needed. We examined the added value of circulating tumor cell (CTC) enumeration relative to common prognostic laboratory measures from patients with CRPC.Methods: Utility of CTC enumeration as a baseline and postbaseline prognostic biomarker was examined using data from two prospective randomized registration-directed trials (COU-AA-301 and ELM-PC4) within statistical models used to estimate risk for survival. Discrimination and calibration were used to measure model predictive accuracy and the added value for CTC enumeration in the context of a Cox model containing albumin, lactate dehydrogenase (LDH), PSA, hemoglobin, and alkaline phosphatase (ALK). Discrimination quantifies how accurately a risk model predicts short-term versus long-term survivors. Calibration measures the closeness of actual survival time to the predicted survival time.Results: Adding CTC enumeration to a model containing albumin, LDH, PSA, hemoglobin, and ALK (“ALPHA”) improved its discriminatory power. The weighted c-index for ALPHA without CTCs was 0.72 (SE, 0.02) versus 0.75 (SE, 0.02) for ALPHA + CTCs. The increase in discrimination was restricted to the lower-risk cohort. In terms of calibration, adding CTCs produced a more accurate model-based prediction of patient survival. The absolute prediction error for ALPHA was 3.95 months (SE, 0.28) versus 3.75 months (SE, 0.22) for ALPHA + CTCs.Conclusions: Addition of CTC enumeration to standard measures provides more accurate assessment of patient risk in terms of baseline and postbaseline prognosis in the mCRPC population. Clin Cancer Res; 23(8); 1967–73. ©2016 AACR.

The source of GD3 impacts CD1d-mediated antigen presentation.(A) LCD1d cells were treated with GD3 from different sources for 4 hours, then washed extensively and cocultured with NKT cell hybridomas. IL-2 was measured, as an indication of NKT cell activation, by standard cytokine ELISA. (B) Pretreatment of a-GalCer loaded aAPC with GD3. a-GalCer loaded aAPC were incubated for 4hr with either medium, GD3, GD2, or ovarian cancer-associated ascites. The aAPC were washed extensively and then cocultured with a Va14+ NKT cell hybridoma, N38-3C3. NKT cell recognition of CD1d was assessed by measuring IL-2 production in the supernatants by ELISA.

Purpose: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.Experimental Design: We conducted a phase I/II study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer, and serum testosterone Results: In phase I (n = 26), no dose-limiting toxicities were observed and 13 of 20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase II (n = 97), 45 of 84 evaluable patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (−7.5 ng/dL) and dehydroepiandrosterone-sulfate (−45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase II patients experienced grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea.Conclusions: 17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses. Clin Cancer Res; 20(5); 1335–44. ©2014 AACR.

PDF file - 65K, Schedule of assessments.

PDF file - 225K, Schematic of Ganglioside GD3 and other glycolipids used or referred to in this paper

We compare the radiative feedbacks resulting from a uniform warming and cooling of sea surface temperatures by 4 K in an ensemble of global climate models. The global-mean net feedback is less stabilising in response to warming in all nine models. This is primarily due to a stronger tropical water vapour feedback, with a smaller contribution from the shortwave cloud feedback. The zonal-mean feedbacks are similarly robust across the ensemble. In the extra-tropics, more positive shortwave cloud feedback under warming is associated with further poleward migration of the mean Southern Hemisphere jet latitude in some models. However, additional experiments with an aquaplanet version of the HadGEM3 model suggest that the asymmetry of the jet shift is not driving that in the cloud feedbacks at these latitudes. In the tropics, stronger water vapour feedback under warming is offset by a weaker shortwave cloud feedback. The result is that the ensemble spread in the differences between the global feedbacks under warming and cooling is mainly determined by their differences in the tropics. The spatial distribution of the feedbacks largely reflects the zonal mean behaviour, although there is considerable intermodel variation in the regional cloud feedbacks, particularly in the tropical shortwave cloud feedback. Comparison with CO2- and solar-forced coupled experiments suggests that the global-mean longwave cloud feedback is nearly invariant to warming and cooling, regardless of the nature of the forcing. The shortwave cloud feedback is generally more positive under warming in the coupled models, consistent with the uniform SST perturbation experiments.

BackgroundGuidelines emphasize rapid antibiotic treatment for sepsis, but infection presence is often uncertain at initial presentation. We investigated the incidence and drivers of false-positive presumptive infection diagnosis among emergency department (ED) patients meeting Sepsis-3 criteria.MethodsFor a retrospective cohort of patients hospitalized after meeting Sepsis-3 criteria (acute organ failure and suspected infection including blood cultures drawn and intravenous antimicrobials administered) in 1 of 4 EDs from 2013 to 2017, trained reviewers first identified the ED-diagnosed source of infection and adjudicated the presence and source of infection on final assessment. Reviewers subsequently adjudicated final infection probability for a randomly selected 10% subset of subjects. Risk factors for false-positive infection diagnosis and its association with 30-day mortality were evaluated using multivariable regression.ResultsOf 8267 patients meeting Sepsis-3 criteria in the ED, 699 (8.5%) did not have an infection on final adjudication and 1488 (18.0%) patients with confirmed infections had a different source of infection diagnosed in the ED versus final adjudication (ie, initial/final source diagnosis discordance). Among the subset of patients whose final infection probability was adjudicated (n = 812), 79 (9.7%) had only “possible” infection and 77 (9.5%) were not infected. Factors associated with false-positive infection diagnosis included hypothermia, altered mental status, comorbidity burden, and an “unknown infection source” diagnosis in the ED (odds ratio: 6.39; 95% confidence interval: 5.14–7.94). False-positive infection diagnosis was not associated with 30-day mortality.ConclusionsIn this large multihospital study

Introduction: Direct-acting oral anticoagulants (DOACs) and warfarin are standard of care for secondary prevention of ischemic stroke (IS) in persons with atrial fibrillation (AF). However, despite adequate anticoagulation (AC), patients may still experience recurrent IS. We aimed to study the characteristics of patients who developed IS despite therapeutic AC, specifically with DOACs. Methods: Between 2012 and 2021, patients admitted at our hospital with IS despite adequate AC for AF were enrolled. Clinical variables collected included National Institute of Health Stroke Scale (NIHSS), CHA 2 DS 2 -VASc and modified Rankin Score (mRS) at admission. Baseline characteristics were compared between patients taking DOACs and warfarin. Logistic regression analyses were performed to identify predictors of IS in patients using DOACs. Results: A total of 595 patients were included. Of these, 291 patients (48.9%) were on DOACs with a mean age of 75.21 and 43.9% were female. The median CHA 2 DS 2 -VASc and NIHSS score in the DOAC group was 4 and 6, respectively. Compared to those on Warfarin, patients on DOACs were younger (75.21 vs. 78.99 p < 0.001), more likely to be men (55.3% vs. 45.2% p = 0.01) and had higher rates of prior TIA/IS (37.5% vs. 29.3% p = 0.04). Both groups had similar rates of hemorrhagic transformation, but more patients in the DOAC group were on antiplatelet agents concomitantly (21% vs. 6.9% p < 0.001). The most prescribed DOAC was apixaban (66.3%) and cardioembolism was the most common stroke etiology (63.6%), followed by cryptogenic, which was significantly higher in the DOAC group (18.2% vs. 8.3% p = 0.02). Notably, DOAC failure in preventing IS was associated with younger age, overweight/obesity, and prior TIA/IS (Table) . Conclusions: IS despite the use of DOACs is more likely to occur in younger people with prior TIA/IS and obesity. Focusing on preventative strategies and risk factor control for competing mechanisms in this subgroup may help prevent IS recurrence.

Mycoviruses may influence the pathogenicity of disease-causing fungi. Although mycoviruses have been found in some chytrid fungi, limited testing has not detected them in Batrachochytrium dendrobatidis (Bd), the cause of the devastating amphibian disease, chytridiomycosis. Here we conducted a survey for mycovirus presence in 38 Bd isolates from Australia (n = 31), Brazil (n = 5) and South Korea (n = 2) with a combination of modern high-throughput sequencing and conventional dsRNA cellulose chromatography. Mycoviruses were not detected in any isolates. This result was unexpected, given the long evolutionary history of Bd, as well as the high prevalence of mycoviruses in related fungal species. Given our widespread sampling in Australia and the limited number of Bd introductions, we suggest that mycoviruses are uncommon or absent from Australian Bd. Testing more isolates from regions where Bd originated, as well as regions with high diversity or low fungal virulence may identify mycoviruses that could aid in disease control.

We demonstrate acousto-optic modulation of a fiber Bragg grating in a birefringent suspended core fiber up to frequencies of 5.2 MHz for the first time. At acoustic resonances lower than 820 kHz, the reflectivity of the orthogonal polarization modes is electrically switched to a superposed reflection band with a maximum modulation depth of 51% at 10 V. The wavelength peak of the polarization modes is dynamically shifted by tuning the driven electrical signal from 1.92 to 5.2 MHz. A novel side-coupled based acousto-optic device is demonstrated, indicating new possibilities for ultracompact, fast and efficient all-fiber integrated devices.